Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome

  • Nature. 2023 Nov 22. doi: 10.1038/s41586-023-06742-w.
Xuyan Shi  #  1 ,  Qichao Sun  #  2  3 ,  Yanjie Hou  2 ,  Huan Zeng  1 ,  Yong Cao  1 ,  Mengqiu Dong  1 ,  Jingjin Ding  4  5  6 ,  Feng Shao  7  8  9  10  11  12
Affiliations
  • 1. National Institute of Biological Sciences, Beijing, Beijing, P. R. China.
  • 2. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China.
  • 3. University of Chinese Academy of Sciences, Beijing, P. R. China.
  • 4. National Institute of Biological Sciences, Beijing, Beijing, P. R. China. [email protected].
  • 5. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China. [email protected].
  • 6. University of Chinese Academy of Sciences, Beijing, P. R. China. [email protected].
  • 7. National Institute of Biological Sciences, Beijing, Beijing, P. R. China. [email protected].
  • 8. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China. [email protected].
  • 9. Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, Beijing, P. R. China. [email protected].
  • 10. Changping Laboratory, Beijing, P. R. China. [email protected].
  • 11. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, P. R. China. [email protected].
  • 12. New Cornerstone Science Laboratory, Shenzhen, P. R. China. [email protected].
  • # Contributed equally.
PMID: 37993714 DOI: 10.1038/s41586-023-06742-w
Abstract

The canonical (Caspase-1) and noncanonical (comprising caspases 4, 5 and 11; hereafter, caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce Pyroptosis1,2. Whereas Caspase-1 processes IL-1β and IL-18 for maturation3-6, no cytokine target has been firmly established for lipopolysaccharide-activated caspase-4/5/117-9. Here we show that activated human caspase-4, but not mouse caspase-11, directly and efficiently processes IL-18 in vitro and during Bacterial infections. Caspase-4 cleaves the same tetrapeptide site in pro-IL-18 as Caspase-1. The crystal structure of the caspase-4-pro-IL-18 complex reveals a two-site (binary) substrate-recognition mechanism; the catalytic pocket engages the tetrapeptide, and a unique exosite that critically recognizes GSDMD10 similarly binds to a specific structure formed jointly by the propeptide and post-cleavage-site sequences in pro-IL-18. This binary recognition is also used by caspase-5 as well as Caspase-1 to process pro-IL-18. In caspase-11, a structural deviation around the exosite underlies its inability to target pro-IL-18, which is restored by rationally designed mutations. The structure of pro-IL-18 features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL-18Rα receptor. Cleavage by Caspase-1, -4 or -5 induces substantial conformational changes of IL-18 to generate two critical receptor-binding sites. Our study establishes IL-18 as a target of lipopolysaccharide-activated caspase-4/5. The finding is paradigm shifting in the understanding of noncanonical-inflammasome-mediated defences and also the function of IL-18 in immunity and disease.

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